The timing of stopping immunotherapy in lung cancer varies depending on progression, AEs, and recovery


For lung cancer patients treated with immunotherapy, there are 3 basic scenarios that dictate discontinuation of treatment: progression, toxicity and cure. However, each situation has its own complex nuances to consider before making the decision to stop treatment, according to a presentation by Matthew D. Hellmann, MD, at the 16th annual New York Symposium on Lung Cancers.1

“There are 3 scenarios in which to stop treatment, some of them may seem simpler than others,” said Hellmann, medical oncologist at Memorial Sloan Kettering Cancer Center. “The first, which may seem the simplest, is to progress when the patient is no longer benefiting from it. Sure, [in most cases] we would stop. But there are some nuances in [terms of] consider whether a patient benefits, both in the context of refractory disease as well as in the context of acquired resistance (AR).

In the case of patients with refractory disease, clinicians should consider the results at the lesion level, according to Hellmann. When treating patients with acquired resistance, oligo vs systemic resistance should be carefully assessed, Hellmann said.

In primary refractory disease, the typical conception when there is a progression defined by RECIST at the first ultrasound would be to discontinue treatment due to lack of benefit. However, lesion heterogeneity may reveal an incomplete or heterogeneous response to PD-1 blockade. In these situations, clinicians should use lesion-level response assessments coupled with biomarker analysis to better interpret efficacy and potentially pursue PD-1 blockade as part of the next line of treatment.

In the Phase 1 KEYNOTE-001 trial (NCT01295827), a study of patients with lung cancer, melanoma, and gastric cancer, there was a cohort of 432 patients with non-small cell lung cancer (NSCLC) of which 41% were considered to be primary refractory to pembrolizumab. Here there was a 60% mixture of growing, stable or shrinking lesions; only 22% of patients had growing lesions at all sites. In addition, a large subset of the population (26%) had at least one narrowing lesion and 8% of patients achieved narrowing in most lesions.2

Hellman noted that the most easily inferred point for stopping immunotherapy in patients with refractory disease is when patients experience growth of all lesions. He stressed that in patients with heterogeneity of lesions, it should be questioned whether pembrolizumab actually provided some benefit and whether continuation in any form would help in the treatment of these patients. About 10% of patients characterized by RECIST as having refractory disease likely benefit primarily from treatment, Hellmann said.

For patients who develop AR on immunotherapy, there may be different patterns that are best reflected when considering responses at the individual lesion level. In an unpublished analysis of patients who developed RA oligo or systemic RA, patients with RA oligo achieved greater post-progression overall survival benefit (P <.001 local therapy also had a benefit in patients with oligo ar>P = .04) compared to systemic treatment. Plus, AR occurring at a single site doesn’t necessarily mean therapy is failing throughout the body, Hellmann said.1

“At a time [refractory and AR], it forces us to think beyond the overall average patient, but instead focus on what is happening at the individual metastasis level or at the lesion level in response to treatment, ”Hellmann explained. “It can shed light on our understanding of what’s going on, what types of drugs work, and how best to continue or stop.”

In terms of toxicity indicating when to stop immunotherapy, treatment should generally be stopped after a serious adverse event related to the immune system. However, when an event occurs at the start of treatment, there may be additional benefit to the patient by resuming treatment. In a study of patients with NSCLC who were retreated with immunotherapy following toxicity, researchers found that there was an overall survival benefit in patients who were retreated (RR: 0, 45; 95% CI: 0.21-1.0; P = 0.049) compared to those who stopped treatment completely. The benefit was mainly seen in patients who exhibited early toxicity.1.3

“It is rarely possible for patients to benefit from re-treatment after toxicity,” Hellmann said. “But it was only the patients who showed early toxicity. Our paradigm has been that if you have early toxicity, and if you are still not sure whether the patient is benefiting from treatment, this is a reasonable place to consider resuming treatment.

In the small number of patients with metastatic disease who are cured following treatment with immune therapy, clinicians must decide whether further treatment is reasonable or necessary.

Hellmann argues that biomarkers such as circulating tumor DNA (ct) are an important factor in determining whether further treatment is needed. In an analysis of 31 patients with NSCLC, the 4 patients with detectable cDNA experienced progression, while a large majority of the 27 patients without detectable cDNA did not progress (P <.0001>4

“We found that if you had detectable cDNA, unfortunately a relapse was likely and was likely to happen soon,” Hellmann concluded. “But, in patients who were negative 1 or 2 years after starting treatment and were still doing well, if no cDNA was detectable, they remained healthy for many years afterward. This fraction of patients may well represent those who are nearing recovery, and for whom we may consider stopping treatment. “

The references

  1. Hellmann M. When to stop immunotherapy. Introduced to : 16th annual New York Symposium on Lung Cancers; November 6, 2021; New York, NY.
  2. Topp BG, Thiagarajan K, De Alwis DP, et al. Lesion heterogeneity of radiological progression in patients treated with pembrolizumab. Anne Oncol. 2021; S0923-7534 (21) 04485-9. doi: 10.1016 / j.annonc.2021.09.006
  3. Santini FC, Rizvi H, Plodkowski AJ, et al. Safety and efficacy of retreatment with immunotherapy after adverse events related to the immune system in patients with NSCLC. Immunol Research. 2018; 6 (9): 1093-1099. do I:10.1158 / 2326-6066.CIR-17-0755
  4. Hellmann MD, Nabet BY, Rizvi H, et al. Analysis of circulating tumor DNA to assess the risk of progression after a long-term response to PD- (L) 1 blockade in NSCLC. Clin Cancer Res. 2020; 26 (12): 2849-2858. doi: 10.1158 / 1078-0432.CCR-19-3418

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